The influenza virus belongs to the Orthomyxoviridae family and is classified into three types: A, B and C according to their internal protein sequences. With the global pandemic potential and up to 500,000 annual deaths worldwide during seasonal epidemics, influenza A virus is a major public health concern and causes enormous economic burden. Prevention relying on vaccination has several limitations, including the lag time for vaccine manufacture and the low coverage rate. Considering the increasing level of viral resistance to current anti-influenza drugs targeting neuraminidase (NA) or M2 channel, it is particularly important to develop novel antiviral medicine.
Interferon (IFN) was discovered in 1957 as an agent that can inhibit (interfere with) the replication of influenza virus. The IFN family of cytokines is now recognized as the most potent vertebrate-derived signals for mobilizing antimicrobial effector functions against intracellular pathogens. Three classes of IFN has been identified and classified according to the receptor complex they signal through: Type I interferons (IFNβ, 14 IFNαs, IFδ, IFNε, IFNκ, IFNo and IFNτ), best known for their antiviral properties, mediate the induction of both the innate immune response and subsequent adaptive immunity to viruses; Type II interferon (IFNγ) stimulates broad immune response to various pathogens other than viruses; and, Type III interferons (3 IFNλs) are also known to regulate antiviral response and are proposed as ancestral type I IFN. It is widely accepted that viral attachment and viral dsRNA intermediates accumulating during virus replication are the primary mediators triggering IFNs production, which ultimately results in expression of thousands of IFN-stimulated genes (ISGs) (OAS1, MX1, etc.) and limits virus replication.
In the early phase of infection, Toll-like receptors, cytosolic RIG-1-like receptors (RIG-1 and MDA5), NOD-like receptors and C-type lectin receptors are major players involved in innate recognition of influenza virus. Recently, the novel IFN-regulated viral RNA sensor interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) was identified as having antiviral properties. Activation of type I IFN expression by these pattern recognition receptors (PRRs) is highly controlled by several transcription factors (TFs) including c-Jun/ATF2 (AP1), interferon regulatory factor 3/7 (IRF3/7), and p50/p65 (NF-κB). Smad3, as a transcription factor, also enhances type I IFN expression by cooperating with IRF7. In the later phase of infection, secreted type I IFN signal stimulates type I IFN receptor (IFNAR1/2) in an autocrine and paracrine fashion, which leads to the activation of Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway, and finally turns on cellular antiviral status.
Axin, which was identified from analysis of the mouse-Fused locus, is a negative regulator of Axis formation in the development of mouse embryos. Axin protein, present in two isoforms (Axin1 and Axin2), acts as an architectural platform for the degradation of the oncogenic protein β-catenin. Axin1 has, in fact, emerged as a multidomain scaffolding protein for many other signaling pathways, including c-Jun-NH2-kinase (JNK) mitogen-activated protein kinase (MAPK) signaling, p53 signaling, and transforming growth factor β (TGF-β) signaling. Axin1 forms a complex with MEKK1/4 and mediates JNK/c-Jun activation through MKK4/7. Axin1 also promotes Smad3 phosphorylation in response to TGF-β, and down-regulates the negative factor, Smad7, in TGF-β signaling. By forming a ternary complex, Axin1 stimulates p53 functions via activation of homeodomain-interacting protein kinase-2 (HIPK2) kinase. These intriguing β-catenin-independent roles of Axin1 open the door to its function in multiple physiological and pathological processes. With respect to infectious diseases, Axin1 apparently displays a preventive effect on bacterial Salmonella invasiveness and modulates inflammatory responses during infection. On the other hand, silencing of Axin1 up-regulates human immunodeficiency virus type I (HIV-1) gene expression and viral replication. Recently, XAV939, termed RN-1 in this study, was discovered to specifically inhibit poly(ADP-ribose) polymerase tankyrase1/2 (TNK1/2), which induces poly(ADP-ribosyl)ation (PARylation) of Axin1 and in turn promotes its proteasome-mediated degradation.
Before proceeding to a description of the present invention, however, it should be noted and remembered that the description of the invention which follows, together with the accompanying drawings, should not be construed as limiting the invention to the examples (or embodiments) shown and described. This is so because those skilled in the art to which the invention pertains will be able to devise other forms of this invention within the ambit of the appended claims.